Theunderlyingcausesofinsulinresistancedifferamongpatients.Threemajorunderlyingcausesofobesity-inducedinsulinresistanceare: 1.Decreased ability of insulin to increase GLUT4-mediated uptake of glucose, especially by skeletal muscle. Thisfunction,whichisspecificallyapartofglucometabolic regulation by insulin, maybeduetoexcessiveaccumulationofTGinmuscleinobeseindividuals.Excessivecaloricintakeinduceshyperinsulinemia.Initiallythisleadstoexcessiveglucoseuptakeintoskeletalmuscle.Justasintheliver,excessivecaloriesintheformofglucosepromotelipogenesisand,throughgenerationofmalonylCoA,repressionoffattyacylCoAoxidation.ByproductsoffattyacidandTGsynthesis(e.g.,diacylglycerol,ceramide)mayaccumulateandstimulatesignalingpathways(e.g.,proteinkinaseC–dependentpathways)thatantagonizesignalingfromtheInsRorIRSproteins,orboth.Thusinsulinresistanceintheskeletalmuscleofobeseindividualsmaybeduetolipotoxicity.
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Decreased ability of insulin to repress hepatic glucose production. Thelivermakesglucosebyglycogenolysisintheshorttermandbygluconeogenesisinthelongterm.Theabilityofinsulintorepresskeyhepaticenzymesinboththesepathwaysisattenuatedininsulin-resistantindividuals.Insulinresistanceinthelivermayalsobeduetolipotoxicityinobeseindividuals(e.g.,fatty liver orhepatic steatosis).Visceraladiposetissueislikelytoaffectinsulinsignalingattheliverinseveralways,inadditiontotheeffectsoflipotoxicity.Forexample,visceraladiposetissuereleasesthecytokinetumor necrosis factor (TNF)-α, whichhasbeenshowntoantagonizeinsulinsignalingpathways.Also,TGinvisceraladiposetissuehasahighrateofturnover(possiblybecauseofrichsympatheticinnervation),sotheliverisexposedtohighlevelsofFFAs,whichfurtherexacerbateshepaticlipotoxicity.
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Inability of insulin to repress hormone-sensitive lipase or increase LPL in adipose tissue (or both). HighHSLandlowLPLaremajorfactorsinthedyslipidemiaassociatedwithinsulinresistanceanddiabetes.AlthoughthefactorsthatresisttheactionsofinsulinonHSLandLPLarenotcompletelyunderstood,thereisevidenceforincreasedproductionofparacrinediabetogenicfactorsinadiposetissue,suchasTNF-α.ThedyslipidemiaischaracterizedashypertriglyceridemiawithlargeTG-richVLDLparticlesproducedbytheliver.BecauseoftheirhighTGcontent,largeVLDLsandIDLsaredigestedveryefficiently,therebygivingrisetosmall,denseLDLparticlesthatareveryatherogenic.Inaddition,HDLtakesonexcessTGinexchangeforcholesterolesters,whichappearstoshortenthecirculatinghalf-lifeofHDLandApoAproteins.ThustherearelowerlevelsofHDLparticles,whichnormallyplayaprotectiveroleagainstvasculardisease.T1DM ischaracterizedbydestructionofbetacells,almost alwaysbyanautoimmunemechanism.T1DMisalsotermedinsulin-dependent diabetes mellitus. CharacteristicsofT1DMare: 1.
PeoplewithT1DMneedexogenousinsulintomaintainlifeandpreventketosis;virtuallynopancreaticinsulinisproduced.
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